{"gene":"SERPINB5","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1996,"finding":"Recombinant maspin binds specifically to the cell surface of mammary carcinoma cells (shown by immunostaining) and inhibits cell motility and invasion; pre-treatment with anti-maspin antibody blocks these effects, but antibody added after cell-surface binding cannot reverse them, indicating maspin activity is membrane-associated.","method":"Time-lapse video microscopy, modified Boyden chamber invasion assays, immunostaining of cell-surface-bound protein, antibody blocking experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays with antibody blocking controls, single lab","pmids":["8876194"],"is_preprint":false},{"year":2000,"finding":"Maspin inhibits angiogenesis: it directly blocks migration, mitogenesis, and tube formation of cultured endothelial cells toward bFGF and VEGF in vitro, and inhibits corneal neovascularization in vivo. Maspin mutants with reactive-site loop (RSL) mutations that lose anti-motility activity against fibroblasts/keratinocytes/cancer cells retain anti-angiogenic activity, indicating the two functions are mechanistically separable.","method":"In vitro endothelial cell migration, mitogenesis, and tube formation assays; rat cornea pocket assay; RSL mutagenesis; xenograft tumor model","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal in vitro and in vivo assays with mutagenesis; replicated across multiple experimental systems","pmids":["10655109"],"is_preprint":false},{"year":2000,"finding":"Wild-type p53 directly binds to a p53 consensus element in the maspin promoter and transcriptionally activates maspin expression; DNA-damaging agents induce endogenous maspin in wild-type p53 cells but not mutant-p53 cells.","method":"Adenoviral p53 overexpression, promoter-reporter assays, EMSA/DNA binding, pharmacological DNA-damage induction in isogenic cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding demonstrated by EMSA, functional reporter assays, and genetic comparison across multiple cell lines","pmids":["10692390"],"is_preprint":false},{"year":2003,"finding":"Maspin inhibits urokinase-type plasminogen activator (uPA)-dependent extracellular matrix degradation in prostate cancer cells; maspin-expressing DU145 transfectants showed reduced ECM and collagen degradation, decreased osteolysis, decreased tumor growth, and decreased angiogenesis in a human fetal bone xenograft model, consistent with maspin blocking the pericellular uPA proteolytic cascade.","method":"In vitro ECM/collagen degradation assays, intratibial injection xenograft model (human fetal bone in immunodeficient mice), histology/immunostaining","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo assays, single lab","pmids":["12788977"],"is_preprint":false},{"year":2003,"finding":"Maspin promoter is controlled by epigenetic mechanisms (DNA methylation and histone deacetylation); treatment of maspin-negative pancreatic cancer cells with 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor) and trichostatin A (HDAC inhibitor) re-activates maspin mRNA expression. Maspin-positive pancreatic carcinoma cells have demethylated promoters with hyperacetylated H3/H4 histones, while maspin-negative cells have methylated, hypoacetylated promoters.","method":"Bisulfite genomic sequencing, chromatin immunoprecipitation (ChIP), 5-aza-dC and TSA pharmacological treatment, luciferase reporter assays","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal epigenetic methods (bisulfite sequencing, ChIP, pharmacological reactivation) in same study","pmids":["14670180"],"is_preprint":false},{"year":2004,"finding":"p63 (specifically TAp63) transcriptionally activates maspin by binding to the p53-binding site on the maspin promoter; maspin expression in lung cancer cell lines is strictly dependent on p63 presence and loss of p63 explains loss of maspin in highly invasive cells.","method":"Transient p63 transfection, maspin promoter-luciferase reporter, EMSA, chromatin immunoprecipitation (ChIP), siRNA/shRNA loss-of-function, cell invasion assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding shown by EMSA and ChIP, functional rescue experiments, multiple cell lines","pmids":["15466179"],"is_preprint":false},{"year":2003,"finding":"Maspin regulates cell motility through the Rho GTPase pathway: exogenous recombinant maspin and stable maspin transfection in MDA-MB-231 cells decreased Rac1 activity within 4 h and reduced its effector PAK1 within 12 h. Maspin also increased PI3K and ERK1/2 activities (PI3K upstream of ERK), promoting cell adhesion via the PI3K/ERK pathway.","method":"Rac1 activity pull-down assay, Western blotting for PAK1/PI3K/ERK, PI3K inhibitor (LY294002) epistasis, cell adhesion and motility assays, phalloidin/focal adhesion staining","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis with pharmacological inhibitor, multiple signaling readouts, single lab","pmids":["14508113"],"is_preprint":false},{"year":2006,"finding":"Maspin physically associates with β1 integrin at the cell membrane to regulate cell adhesion; maspin co-localizes with detergent-insoluble cortical cytoskeleton elements (adhesion plaque), and a domain of 86 amino acids (aa 139–225) is required for this adhesion effect. Maspin knockdown by RNAi reduces adhesion, and the effect is β1 integrin-dependent.","method":"Co-immunoprecipitation, RNAi knockdown, recombinant protein deletion/mutation analysis, adhesion assays, subcellular fractionation","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and domain mapping with RNAi validation, single lab","pmids":["16720730"],"is_preprint":false},{"year":2006,"finding":"Maspin binds directly to pro-uPA (K_d ≈ 270 nM), inhibits plasmin-mediated pro-uPA cleavage, and promotes internalization of the uPA/uPAR complex; this requires the maspin RSL P1' Arg340, since R340A mutation abolishes both pro-uPA binding and the maspin effects on pro-uPA cleavage and cell detachment. Maspin also enhances the uPAR–LRP interaction and sustains mature focal adhesion contacts.","method":"Biophysical binding assay (K_d determination), plasmin cleavage assay, site-directed mutagenesis of RSL, co-localization immunofluorescence, cell detachment/adhesion assays, Co-IP","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding with K_d measurement, enzymatic inhibition assay, mutagenesis validation, and cellular functional readouts in one study","pmids":["16618739"],"is_preprint":false},{"year":2005,"finding":"Intracellular maspin overexpression in endothelial cells induces apoptosis involving changes in Bcl-2 family gene expression and caspase activation; this effect is dependent on the RSL region of maspin and is blocked by Bcl-2 overexpression or caspase inhibitors. Tumor neovessels (but not mature normal vessels) are disrupted by intravascular adenoviral maspin delivery in mice.","method":"Adenoviral overexpression in vitro and in vivo, apoptosis assays, caspase inhibitor blockade, Bcl-2 overexpression rescue, maspin RSL deletion mutants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with Bcl-2 overexpression and caspase inhibitors, RSL mutagenesis, in vivo confirmation; single lab","pmids":["15688005"],"is_preprint":false},{"year":2010,"finding":"In non-transformed human epithelial cells (MCF10A, RWPE-1), maspin has an obligate intracellular, nucleocytoplasmic distribution; it is neither glycosylated nor secreted, not present at the cell surface (cell-surface biotinylation negative), not associated with the cytoskeleton, and exists as a soluble monomer. Addition of a signal peptide directs maspin into the secretory pathway producing glycosylation but not secretion.","method":"Indirect immunofluorescence, immunoblotting, pulse-chase glycosylation analysis, cell-surface biotinylation, subcellular fractionation, 3D acini differentiation, signal-peptide fusion construct","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods (biotinylation, pulse-chase, fractionation, 3D model) in single rigorous study","pmids":["20123984"],"is_preprint":false},{"year":2010,"finding":"Maspin enhances endothelial cell (HUVEC) adhesion through integrin β1 activation, which redistributes vinculin and F-actin and increases integrin-linked kinase (ILK) activity and FAK phosphorylation. During bFGF-stimulated migration, maspin decreases active Rac1 and Cdc42, elevates FAK-Tyr397 phosphorylation, reduces focal adhesion disassembly, and retards EC migration.","method":"Integrin activation assays, ILK activity assay, phospho-FAK Western blotting, Rac1/Cdc42 pull-down, F-actin/vinculin immunostaining, HUVEC migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts of integrin signaling, single lab","pmids":["20713357"],"is_preprint":false},{"year":2010,"finding":"The G α-helix of maspin is essential and sufficient for inhibiting cell migration and regulating cell adhesion; a 15-mer G-helix peptide mimics maspin's anti-migratory effect, and G-helix mutations abolish it. These G-helix effects depend on β1 integrins. Mutations at the P1 reactive center loop position or an internal salt bridge do not attenuate cell migration inhibition.","method":"Site-directed mutagenesis of G-helix, salt bridge, and P1 positions; synthetic peptide; cell migration and adhesion assays; integrin-blocking antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis plus synthetic peptide reconstitution identifies sufficient structural element; β1 integrin dependence confirmed","pmids":["20837467"],"is_preprint":false},{"year":2010,"finding":"PAR-1 (thrombin receptor) negatively regulates maspin transcription in metastatic melanoma by reducing binding of Ets-1 and c-Jun to the maspin promoter; PAR-1 silencing increases CBP/p300 expression and decreases p38 activity, leading to enhanced Ets-1/c-Jun binding and maspin re-expression, which reduces melanoma invasiveness.","method":"Gene expression profiling, promoter-luciferase reporter, ChIP for Ets-1/c-Jun, CBP/p300 and p38 Western blotting, siRNA silencing, invasion assays, xenograft tumor models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP for transcription factor binding, epistasis by PAR-1 rescue, multiple in vitro and in vivo functional readouts","pmids":["21187389"],"is_preprint":false},{"year":2011,"finding":"Maspin inhibits HDAC1 and thereby increases acetylation of Ku70, causing dissociation of Bax from Ku70 and triggering Bax-dependent apoptosis. Maspin was identified as a Ku70-interacting molecule.","method":"HDAC1 activity assay, Ku70 acetylation Western blotting, Co-immunoprecipitation of maspin-Ku70 and Bax-Ku70 interactions, cell death assays","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and enzymatic activity assay linking maspin to HDAC1 inhibition and Ku70 acetylation; single lab","pmids":["22076034"],"is_preprint":false},{"year":2011,"finding":"SerpinB5/maspin physically interacts with KHDRBS3 and FBXO32 in gastric cancer cells (confirmed by co-immunoprecipitation and yeast two-hybrid); KHDRBS3 in turn interacts with FBXO32 mRNA (RNA Co-IP), and changes in SerpinB5 expression alter FBXO32 mRNA levels 24 h after KHDRBS3 protein levels change.","method":"Yeast two-hybrid screening, co-immunoprecipitation, RNA co-immunoprecipitation, RNAi knockdown, Western blotting, RT-PCR","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and RNA Co-IP validating yeast two-hybrid hits; single lab","pmids":["21725612"],"is_preprint":false},{"year":2007,"finding":"Maspin expression is induced by proteasome inhibitors via a p38MAPK/AP-1 pathway; maspin siRNA attenuates proteasome inhibitor-induced apoptosis, and maspin-transfected prostate cancer cells show enhanced apoptosis with proteasome inhibitors. AP-1 activation by p38MAPK (not ERK1/2 or NF-κB) drives maspin transcription.","method":"EMSA, promoter-reporter assays, p38MAPK/ERK/NF-κB inhibitors for pathway epistasis, maspin siRNA knockdown, apoptosis assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding by EMSA, pharmacological epistasis, siRNA validation; single lab","pmids":["17458898"],"is_preprint":false},{"year":2009,"finding":"PTEN and p53 act in tandem to induce maspin expression under hypoxia: nuclear PTEN complexes with p53, while cytoplasmic PTEN prevents Mdm2 nuclear entry (by attenuating Akt), protecting p53 from degradation. Combined PTEN/p53 presence coordinates maspin and p21 induction. Altering PTEN or p53 expression attenuated maspin induction.","method":"Subcellular fractionation, Co-IP of PTEN-p53 complex, Akt inhibition, genetic knockdown of PTEN and p53, immunohistochemistry of xenograft tumors, Western blotting","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic epistasis (double knockdown) and in vivo IHC confirmation; single lab","pmids":["19221500"],"is_preprint":false},{"year":2008,"finding":"Maspin enhances sensitivity of prostate cancer cells to hypoxia-induced apoptosis; maspin-overexpressing DU-145 cells show increased apoptosis and reduced tumor growth/vascularity under hypoxia, with suppression of Akt and focal adhesion kinase (FAK) activation as the mechanistic basis.","method":"Maspin stable transfection, hypoxia chamber (1% O2), apoptosis assays, phospho-Akt/FAK Western blotting, in vivo xenograft tumor growth and vascularity analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic overexpression with in vivo confirmation and defined signaling readout (Akt/FAK); single lab","pmids":["18931702"],"is_preprint":false},{"year":2012,"finding":"Maspin downregulation (by shRNA or E2F1-DP1 overexpression) dramatically accelerates cell cycle progression in gastric cancer cells with increased active CDC25C and decreased inactive CDK1, while maspin upregulation retards cell proliferation, establishing maspin as a cell cycle regulator.","method":"shRNA knockdown, E2F1-DP1 overexpression, flow cytometry cell cycle analysis, Western blotting for CDC25C and CDK1 phosphorylation states","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal loss-of-function approaches (shRNA and E2F1-DP1 OE) with specific cell cycle molecular readouts; single lab","pmids":["22962304"],"is_preprint":false},{"year":2014,"finding":"Myocardin activates maspin transcription through a CArG box in the maspin promoter; this is demonstrated by luciferase reporter assay. Combined treatment with 5-aza-dC/TSA (epigenetic de-repression) and myocardin synergistically enhances maspin re-expression and maspin-mediated apoptosis in MCF-7 breast cancer cells.","method":"Luciferase reporter assay with CArG box mutagenesis, myocardin transfection, 5-aza-dC/TSA epigenetic drug treatment, apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter element identification by reporter assay with mutagenesis; single lab","pmids":["24607789"],"is_preprint":false},{"year":2016,"finding":"EGFR ligands (EGF, TGFα) regulate maspin/SerpinB5 phosphorylation in mammary epithelial cells; EGF specifically induces SerpinB5 nuclear accumulation. At least 8 different SerpinB5 phosphoforms were detected by high-resolution isoelectric focusing during lactation. Amphiregulin autocrine activity maintains basal phosphorylation.","method":"High-resolution isoelectric focusing/immunoblot for phosphoform detection, EGF/TGFα treatment, nuclear fractionation/imaging for localization, EGFR ligand blocking experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical detection of phosphoforms plus ligand-stimulated nuclear translocation; single lab, single study","pmids":["27447178"],"is_preprint":false},{"year":2020,"finding":"SERPINB5/maspin acts as an adaptor protein in the TRIM21-SERPINB5-GMPS complex: SERPINB5 prevents GMPS from entering the nucleus and recruits TRIM21 (an E3 ubiquitin ligase) to ubiquitinate and degrade GMPS, thereby repressing TP53 expression and promoting radioresistance in nasopharyngeal carcinoma cells.","method":"Mass spectrometry identification of TRIM21 targets, Co-immunoprecipitation of TRIM21-SERPINB5-GMPS complex, CRISPR knockout and overexpression, flow cytometry, immunofluorescence for subcellular localization, in vivo xenograft","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of trimeric complex, CRISPR genetics, in vivo confirmation; single lab","pmids":["32005234"],"is_preprint":false},{"year":2020,"finding":"Maspin inhibits EMT and angiogenesis in gastric cancer by blocking the ITGB1/FAK signaling pathway; maspin overexpression decreases ITGB1 and p-FAK, reduces Vimentin and VEGF while increasing E-cadherin, and maspin knockdown restores these phenotypes even when ITGB1 is silenced.","method":"CRISPR activation, siRNA knockdown, Western blotting, tube formation assay, Transwell invasion/migration, wound healing assay, IHC of patient tissues","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double-siRNA (maspin + ITGB1), multiple cellular functional assays; single lab","pmids":["32409959"],"is_preprint":false},{"year":2020,"finding":"Class I HDACs (specifically HDAC1 and HDAC8) repress maspin in prostate cancer cells independent of promoter DNA hypermethylation; HDAC inhibitors (sodium butyrate, TSA) re-express maspin, and this is accompanied by p53 enrichment at the maspin promoter with increased H3/H4 acetylation, suppressing prostate cancer cell proliferation and migration.","method":"HDAC inhibitor treatment (sodium butyrate, TSA), ChIP for p53 and acetyl-H3/H4 at maspin promoter, HDAC1/HDAC8 siRNA knockdown, methylation analysis, proliferation and migration assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence for p53 recruitment and histone acetylation, HDAC-specific knockdown; single lab","pmids":["32391971"],"is_preprint":false},{"year":2014,"finding":"Tamoxifen induces maspin expression through estrogen receptor alpha (ERα) but not ERβ; this requires the ERα LBD-AF2 domain (LBDmtL539A mutation abolishes activation) and cis-elements between -90 and +87 bp of the maspin promoter (not the HRE at -272 bp). The ERα N-terminal AF-1 domain is critical for basal maspin transcription activation.","method":"Maspin-luciferase reporter assay, ERα/ERβ reconstitution in cell culture, ERα deletion/point mutants, promoter deletion analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis and domain-mapping by promoter-reporter, single lab","pmids":["15145521"],"is_preprint":false},{"year":2017,"finding":"Maspin is secreted as an exosome cargo protein: electron microscopy shows maspin encapsulated within the exosomal membrane. Maspin-devoid exosomes (from maspin-knockdown MCF-10A cells) have significantly reduced suppressive effects on chemotaxis of recipient NIH3T3 fibroblasts, demonstrating that exosomal maspin can suppress tumor-induced stromal responses.","method":"Exosome isolation/fractionation, electron microscopy, atomic force microscopy, dynamic light scattering, Western blotting of exosome fractions, maspin siRNA knockdown, NIH3T3 fibroblast chemotaxis assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural visualization by EM, functional knockdown assay in recipient cells; single lab","pmids":["28009978"],"is_preprint":false},{"year":2014,"finding":"Maspin re-expression in prostate tumor cells does NOT inhibit tumor growth or metastasis in vivo and does not influence cell migration, invasion, or survival in vitro in a conditional knockout study; maspin knockout mice develop into overtly normal adults, contrary to original reports of embryonic lethality. Bioinformatic analyses show maspin is not commonly under-expressed in cancer.","method":"Conditional knockout mouse generation, tumor growth/metastasis assays in vivo, cell migration/invasion/survival assays in vitro, bioinformatic expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple independent in vivo and in vitro experiments with conditional KO model; directly contradicts prior overexpression studies","pmids":["24445777"],"is_preprint":false},{"year":2016,"finding":"Maspin deficiency in mice (exon 4 deletion) causes pulmonary adenocarcinoma, mammary myoepithelial hyperplasia, prostatic luminal hyperplasia, and alopecia areata, establishing context-specific tumor suppressor roles for maspin in vivo.","method":"Conditional knockout mouse generation (exon 4 deletion), breeding scheme to bypass embryonic lethality, histopathological phenotyping","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — well-characterized KO mouse model with tissue-specific phenotypes; single lab","pmids":["27923833"],"is_preprint":false},{"year":2024,"finding":"SERPINB5 promotes invasion and migration of colorectal cancer cells by activating the TNF-α/NF-κB pathway (increasing p-NF-κB/p65, N-cadherin, MMP2, MMP9, VEGFA and decreasing E-cadherin); these effects were reversed by QNZ (NF-κB inhibitor), placing SERPINB5 upstream of NF-κB in this pro-tumorigenic context.","method":"Lentiviral overexpression/knockdown, Western blotting, Transwell invasion/migration, proliferation assays, HUVEC tube formation assay, NF-κB pathway inhibitor (QNZ) epistasis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with NF-κB inhibitor and bidirectional expression manipulation; single lab","pmids":["38460302"],"is_preprint":false}],"current_model":"SERPINB5/maspin is an epithelial-specific, primarily intracellular (nucleocytoplasmic) non-inhibitory serpin that suppresses tumor invasion and angiogenesis through multiple context-dependent mechanisms: extracellularly it binds pro-uPA (K_d ~270 nM) via its reactive site loop to inhibit pericellular proteolysis and cell detachment, and engages β1 integrin through its G α-helix to regulate cell adhesion and migration; intracellularly it inhibits HDAC1 (thereby acetylating Ku70, releasing Bax for apoptosis, and maintaining histone acetylation at epithelial gene loci), and can act as an adaptor in a TRIM21–SERPINB5–GMPS ubiquitination complex; its transcription is activated by p53, p63, TAp63, tamoxifen-bound ERα, and myocardin acting on its promoter, and is silenced by promoter DNA methylation and HDAC1/8-mediated histone deacetylation; it is also secreted as an exosome cargo protein capable of suppressing stromal responses, and a conditional knockout mouse model demonstrates context-specific tumor suppressor roles in lung, mammary, and prostatic epithelia."},"narrative":{"mechanistic_narrative":"SERPINB5 (maspin) is an epithelial non-inhibitory serpin that modulates cell adhesion, migration, invasion, angiogenesis, and apoptosis in a context-dependent manner, predominantly as an intracellular nucleocytoplasmic protein [PMID:20123984, PMID:10655109]. In non-transformed epithelial cells maspin is an obligate soluble cytoplasmic and nuclear monomer that is neither glycosylated, cytoskeleton-associated, nor secreted via the classical pathway [PMID:20123984], and EGFR ligands drive its phosphorylation and EGF-stimulated nuclear accumulation [PMID:27447178]. Extracellularly, maspin binds pro-uPA directly via its reactive-site-loop residue Arg340, inhibiting plasmin-mediated pro-uPA cleavage and promoting uPA/uPAR internalization to restrain pericellular proteolysis and cell detachment [PMID:16618739], and it physically associates with β1 integrin to regulate adhesion through a function localized to its G α-helix, which is sufficient to reproduce the anti-migratory effect [PMID:16720730, PMID:20837467]; downstream it suppresses Rac1/Cdc42 and modulates FAK/ILK and PI3K/ERK signaling [PMID:14508113, PMID:20713357]. Maspin's anti-angiogenic activity is mechanistically separable from its anti-motility activity, as RSL mutants that lose anti-motility function retain inhibition of endothelial migration and tube formation [PMID:10655109]. Intracellularly maspin functions in apoptosis and chromatin-linked regulation by inhibiting HDAC1, which acetylates Ku70 and releases Bax to trigger Bax-dependent death [PMID:22076034, PMID:15688005], and it can act as an adaptor in a TRIM21–SERPINB5–GMPS complex that drives GMPS ubiquitination and represses TP53 [PMID:32005234]. Its transcription is activated by p53, TAp63, tamoxifen-bound ERα, and myocardin, and is silenced by promoter DNA methylation and HDAC1/8-mediated histone deacetylation [PMID:10692390, PMID:15466179, PMID:15145521, PMID:24607789, PMID:14670180, PMID:32391971]. A conditional knockout establishes context-specific tumor suppression in lung, mammary, and prostatic epithelia [PMID:27923833], though a separate knockout study found no effect of maspin re-expression on prostate tumor growth, invasion, or survival, indicating its tumor-suppressor role is highly context-dependent [PMID:24445777].","teleology":[{"year":1996,"claim":"Established that maspin acts at the cell surface to restrain tumor cell motility and invasion, framing it as a candidate suppressor of carcinoma invasiveness.","evidence":"Recombinant protein, time-lapse microscopy, Boyden chamber invasion, and antibody-blocking in mammary carcinoma cells","pmids":["8876194"],"confidence":"Medium","gaps":["No molecular surface receptor identified","Mechanism downstream of membrane binding unresolved"]},{"year":2000,"claim":"Separated maspin's anti-angiogenic activity from its anti-motility activity, showing two genetically dissociable functions.","evidence":"Endothelial migration/tube assays, corneal pocket assay, RSL mutagenesis, xenograft","pmids":["10655109"],"confidence":"High","gaps":["Endothelial receptor/target for anti-angiogenic effect not defined","Structural basis of separability unmapped"]},{"year":2000,"claim":"Identified maspin as a direct p53 transcriptional target, linking its induction to the DNA-damage/tumor-suppressor program.","evidence":"Promoter-reporter, EMSA, adenoviral p53, isogenic p53 cell lines","pmids":["10692390"],"confidence":"High","gaps":["Does not address protein-level function","Tissue specificity of p53 control unclear"]},{"year":2003,"claim":"Demonstrated that maspin transcription is epigenetically gated by DNA methylation and histone acetylation, explaining its silencing in cancers.","evidence":"Bisulfite sequencing, ChIP, 5-aza-dC/TSA reactivation, reporter assays in pancreatic cancer cells","pmids":["14670180"],"confidence":"High","gaps":["Does not identify the writers/readers targeting the locus","Causal order of methylation vs deacetylation unresolved"]},{"year":2003,"claim":"Connected maspin to extracellular uPA-dependent proteolysis and to intracellular Rho-family/PI3K-ERK signaling controlling adhesion and motility.","evidence":"ECM/collagen degradation, bone xenograft (uPA); Rac1 pull-down, PI3K/ERK inhibitor epistasis (signaling)","pmids":["12788977","14508113"],"confidence":"Medium","gaps":["Direct biochemical maspin-uPA interaction not yet shown at this stage","Link between surface binding and intracellular signaling unclear"]},{"year":2004,"claim":"Showed TAp63 activates maspin via the p53 site, explaining maspin loss when p63 is lost in invasive cells.","evidence":"p63 transfection, reporter, EMSA, ChIP, siRNA loss-of-function, invasion assays in lung cancer","pmids":["15466179"],"confidence":"High","gaps":["Relative contribution of p53 vs p63 in vivo not resolved","Isoform-specific control beyond TAp63 not addressed"]},{"year":2006,"claim":"Provided the direct biochemical mechanism for extracellular maspin: RSL Arg340-dependent pro-uPA binding that blocks its activation and promotes uPA/uPAR internalization.","evidence":"K_d determination, plasmin cleavage assay, R340A mutagenesis, Co-IP, immunofluorescence","pmids":["16618739"],"confidence":"High","gaps":["Reconciliation with non-secreted intracellular pool not addressed","Stoichiometry within the uPAR-LRP complex unclear"]},{"year":2006,"claim":"Identified β1 integrin as a maspin partner controlling adhesion and mapped a required region (aa 139-225).","evidence":"Co-IP, RNAi, deletion mapping, adhesion assays, fractionation","pmids":["16720730"],"confidence":"Medium","gaps":["Direct vs indirect integrin binding not distinguished","Single lab, no reciprocal structural validation"]},{"year":2010,"claim":"Refined the localization model, showing maspin is an obligate intracellular nucleocytoplasmic monomer in non-transformed epithelium, challenging the secreted/cell-surface model.","evidence":"Immunofluorescence, pulse-chase glycosylation, surface biotinylation, fractionation, 3D acini, signal-peptide fusion","pmids":["20123984"],"confidence":"High","gaps":["How intracellular maspin reaches extracellular targets unresolved","Reconciliation with surface-binding reports incomplete"]},{"year":2010,"claim":"Localized maspin's anti-migratory/adhesion activity to the G α-helix, sufficient as a synthetic peptide and dependent on β1 integrins, distinct from the RSL.","evidence":"G-helix and P1 mutagenesis, 15-mer peptide reconstitution, integrin-blocking antibodies, migration/adhesion assays; endothelial integrin/ILK/FAK signaling","pmids":["20837467","20713357"],"confidence":"High","gaps":["Structural details of G-helix/integrin contact unknown","Integration of G-helix and RSL functions unresolved"]},{"year":2011,"claim":"Defined an intracellular maspin pro-apoptotic mechanism via HDAC1 inhibition, Ku70 acetylation, and Bax release.","evidence":"HDAC1 activity assay, Ku70/Bax Co-IP, acetylation Western, cell death assays","pmids":["22076034"],"confidence":"Medium","gaps":["Direct maspin-HDAC1 binding stoichiometry not defined","Generality across cell types not tested"]},{"year":2011,"claim":"Identified maspin protein interactions with KHDRBS3 and FBXO32 linking it to an RNA-binding/ubiquitin-ligase axis in gastric cancer.","evidence":"Yeast two-hybrid, reciprocal Co-IP, RNA Co-IP, RNAi, RT-PCR","pmids":["21725612"],"confidence":"Medium","gaps":["Functional consequence of FBXO32 mRNA change unclear","Single lab, mechanism downstream undefined"]},{"year":2014,"claim":"Expanded transcriptional control to ERα/tamoxifen and myocardin, mapping responsive promoter elements and domains.","evidence":"Promoter-reporter with element/domain mutagenesis, ERα/ERβ reconstitution, myocardin transfection, epigenetic drug synergy","pmids":["15145521","24607789"],"confidence":"Medium","gaps":["In vivo relevance of these regulators untested","Combinatorial logic with p53/p63 unresolved"]},{"year":2014,"claim":"A conditional knockout challenged the tumor-suppressor model, finding maspin re-expression did not affect prostate tumor growth, invasion, or survival.","evidence":"Conditional KO mice, in vivo tumor/metastasis assays, in vitro migration/invasion/survival, bioinformatic expression analysis","pmids":["24445777"],"confidence":"High","gaps":["Cannot exclude context-specific suppressor roles in other tissues","Mechanism for discrepancy with overexpression studies unresolved"]},{"year":2016,"claim":"Linked EGFR signaling to maspin phosphorylation and EGF-driven nuclear accumulation, indicating regulated subcellular partitioning.","evidence":"High-resolution IEF phosphoform detection, EGF/TGFα treatment, nuclear fractionation, ligand blocking","pmids":["27447178"],"confidence":"Medium","gaps":["Functional consequence of specific phosphoforms unknown","Kinases responsible not identified"]},{"year":2016,"claim":"Genetically established tissue-specific tumor-suppressor phenotypes for maspin loss in lung, mammary, and prostatic epithelia.","evidence":"Exon-4-deletion knockout mouse, breeding to bypass lethality, histopathology","pmids":["27923833"],"confidence":"Medium","gaps":["Molecular drivers of each tissue phenotype undefined","Reconciliation with the negative conditional KO study unresolved"]},{"year":2017,"claim":"Showed maspin is exported as functional exosome cargo capable of suppressing stromal fibroblast chemotaxis, offering a route for non-classical secretion.","evidence":"Exosome isolation, EM/AFM, knockdown, recipient NIH3T3 chemotaxis assay","pmids":["28009978"],"confidence":"Medium","gaps":["Loading mechanism into exosomes unknown","Receptor on recipient cells unidentified"]},{"year":2020,"claim":"Recast maspin as a molecular adaptor in a TRIM21-SERPINB5-GMPS ubiquitination complex that represses TP53 and confers radioresistance.","evidence":"Mass spectrometry, Co-IP of trimeric complex, CRISPR KO/overexpression, localization imaging, xenograft","pmids":["32005234"],"confidence":"Medium","gaps":["Direct binding interfaces not mapped","Tissue generality of this oncogenic role untested"]},{"year":2020,"claim":"Reinforced the β1-integrin/FAK axis as a node through which maspin suppresses EMT and angiogenesis, and confirmed HDAC1/8 (not just methylation) as repressors via p53/histone-acetylation at the promoter.","evidence":"CRISPRa/siRNA epistasis with ITGB1, functional tumor assays (gastric); HDAC inhibitor and HDAC1/8 knockdown with ChIP (prostate)","pmids":["32409959","32391971"],"confidence":"Medium","gaps":["Whether intracellular or extracellular maspin pool drives these effects unclear","Single-lab studies"]},{"year":2024,"claim":"Demonstrated a pro-tumorigenic context where SERPINB5 drives invasion via TNF-α/NF-κB activation, underscoring its context-dependent duality.","evidence":"Lentiviral overexpression/knockdown, NF-κB inhibitor (QNZ) epistasis, invasion/tube formation assays in colorectal cancer","pmids":["38460302"],"confidence":"Medium","gaps":["Mechanism by which SERPINB5 activates NF-κB undefined","Reconciliation with tumor-suppressor contexts unresolved"]},{"year":null,"claim":"How maspin's intracellular nucleocytoplasmic pool, exosomal export, and extracellular receptor engagement are mechanistically unified — and what determines its switch between tumor-suppressive and pro-tumorigenic outputs — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating G-helix/RSL functions","Determinants of context-dependent direction of effect unknown","Mechanism of non-classical secretion vs obligate intracellular localization unreconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[14,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[22,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,21]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[26]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,11,23,29]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,9,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,5,25,20,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,24,14]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,8]}],"complexes":["TRIM21–SERPINB5–GMPS complex"],"partners":["PLAU","ITGB1","HDAC1","XRCC6","TRIM21","GMPS","KHDRBS3","FBXO32"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P36952","full_name":"Serpin B5","aliases":["Maspin","Peptidase inhibitor 5","PI-5"],"length_aa":375,"mass_kda":42.1,"function":"Tumor suppressor. 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Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/18236066","citation_count":21,"is_preprint":false},{"pmid":"15250837","id":"PMC_15250837","title":"Maspin expression in normal and neoplastic salivary gland.","date":"2004","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15250837","citation_count":21,"is_preprint":false},{"pmid":"27923833","id":"PMC_27923833","title":"An Essential Role of Maspin in Embryogenesis and Tumor Suppression.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27923833","citation_count":20,"is_preprint":false},{"pmid":"21496280","id":"PMC_21496280","title":"Maspin expression is frequent and correlates with basal markers in triple-negative breast cancer.","date":"2011","source":"Diagnostic 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cells.","date":"2011","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22076034","citation_count":17,"is_preprint":false},{"pmid":"22825520","id":"PMC_22825520","title":"Predictive value of maspin and Ki-67 expression in transurethral resection specimens in patients with T1 bladder cancer.","date":"2012","source":"Tumori","url":"https://pubmed.ncbi.nlm.nih.gov/22825520","citation_count":17,"is_preprint":false},{"pmid":"31564075","id":"PMC_31564075","title":"Pi5 and Pii Paired NLRs Are Functionally Exchangeable and Confer Similar Disease Resistance Specificity.","date":"2019","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/31564075","citation_count":16,"is_preprint":false},{"pmid":"26067133","id":"PMC_26067133","title":"Maspin-related Orchestration of Aggressiveness of Gastric Cancer.","date":"2016","source":"Applied immunohistochemistry & molecular morphology : 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in 8q24.21 Involved in the Tumorigenesis of Colorectal Cancer by Targeting MASPIN.","date":"2024","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/39082173","citation_count":15,"is_preprint":false},{"pmid":"16751302","id":"PMC_16751302","title":"Simultaneous evaluation of maspin and CXCR4 in patients with breast cancer.","date":"2006","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16751302","citation_count":15,"is_preprint":false},{"pmid":"32391558","id":"PMC_32391558","title":"The roles of MASPIN expression and subcellular localization in non-small cell lung cancer.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32391558","citation_count":14,"is_preprint":false},{"pmid":"24030740","id":"PMC_24030740","title":"Maspin expression and melanoma progression: a matter of sub-cellular localization.","date":"2013","source":"Modern pathology : an official journal of the United States and Canadian 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Mammary Epithelial Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27447178","citation_count":12,"is_preprint":false},{"pmid":"26646275","id":"PMC_26646275","title":"SERPINB5 Promoter Hypomethylation Differentiates Pancreatic Ductal Adenocarcinoma From Pancreatitis.","date":"2016","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/26646275","citation_count":12,"is_preprint":false},{"pmid":"32864042","id":"PMC_32864042","title":"Maspin subcellular expression in wild-type and mutant TP53 gastric cancers.","date":"2020","source":"World journal of gastrointestinal 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video microscopy, modified Boyden chamber invasion assays, immunostaining of cell-surface-bound protein, antibody blocking experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays with antibody blocking controls, single lab\",\n      \"pmids\": [\"8876194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Maspin inhibits angiogenesis: it directly blocks migration, mitogenesis, and tube formation of cultured endothelial cells toward bFGF and VEGF in vitro, and inhibits corneal neovascularization in vivo. Maspin mutants with reactive-site loop (RSL) mutations that lose anti-motility activity against fibroblasts/keratinocytes/cancer cells retain anti-angiogenic activity, indicating the two functions are mechanistically separable.\",\n      \"method\": \"In vitro endothelial cell migration, mitogenesis, and tube formation assays; rat cornea pocket assay; RSL mutagenesis; xenograft tumor model\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal in vitro and in vivo assays with mutagenesis; replicated across multiple experimental systems\",\n      \"pmids\": [\"10655109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Wild-type p53 directly binds to a p53 consensus element in the maspin promoter and transcriptionally activates maspin expression; DNA-damaging agents induce endogenous maspin in wild-type p53 cells but not mutant-p53 cells.\",\n      \"method\": \"Adenoviral p53 overexpression, promoter-reporter assays, EMSA/DNA binding, pharmacological DNA-damage induction in isogenic cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding demonstrated by EMSA, functional reporter assays, and genetic comparison across multiple cell lines\",\n      \"pmids\": [\"10692390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Maspin inhibits urokinase-type plasminogen activator (uPA)-dependent extracellular matrix degradation in prostate cancer cells; maspin-expressing DU145 transfectants showed reduced ECM and collagen degradation, decreased osteolysis, decreased tumor growth, and decreased angiogenesis in a human fetal bone xenograft model, consistent with maspin blocking the pericellular uPA proteolytic cascade.\",\n      \"method\": \"In vitro ECM/collagen degradation assays, intratibial injection xenograft model (human fetal bone in immunodeficient mice), histology/immunostaining\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"12788977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Maspin promoter is controlled by epigenetic mechanisms (DNA methylation and histone deacetylation); treatment of maspin-negative pancreatic cancer cells with 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor) and trichostatin A (HDAC inhibitor) re-activates maspin mRNA expression. Maspin-positive pancreatic carcinoma cells have demethylated promoters with hyperacetylated H3/H4 histones, while maspin-negative cells have methylated, hypoacetylated promoters.\",\n      \"method\": \"Bisulfite genomic sequencing, chromatin immunoprecipitation (ChIP), 5-aza-dC and TSA pharmacological treatment, luciferase reporter assays\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal epigenetic methods (bisulfite sequencing, ChIP, pharmacological reactivation) in same study\",\n      \"pmids\": [\"14670180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"p63 (specifically TAp63) transcriptionally activates maspin by binding to the p53-binding site on the maspin promoter; maspin expression in lung cancer cell lines is strictly dependent on p63 presence and loss of p63 explains loss of maspin in highly invasive cells.\",\n      \"method\": \"Transient p63 transfection, maspin promoter-luciferase reporter, EMSA, chromatin immunoprecipitation (ChIP), siRNA/shRNA loss-of-function, cell invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding shown by EMSA and ChIP, functional rescue experiments, multiple cell lines\",\n      \"pmids\": [\"15466179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Maspin regulates cell motility through the Rho GTPase pathway: exogenous recombinant maspin and stable maspin transfection in MDA-MB-231 cells decreased Rac1 activity within 4 h and reduced its effector PAK1 within 12 h. Maspin also increased PI3K and ERK1/2 activities (PI3K upstream of ERK), promoting cell adhesion via the PI3K/ERK pathway.\",\n      \"method\": \"Rac1 activity pull-down assay, Western blotting for PAK1/PI3K/ERK, PI3K inhibitor (LY294002) epistasis, cell adhesion and motility assays, phalloidin/focal adhesion staining\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis with pharmacological inhibitor, multiple signaling readouts, single lab\",\n      \"pmids\": [\"14508113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Maspin physically associates with β1 integrin at the cell membrane to regulate cell adhesion; maspin co-localizes with detergent-insoluble cortical cytoskeleton elements (adhesion plaque), and a domain of 86 amino acids (aa 139–225) is required for this adhesion effect. Maspin knockdown by RNAi reduces adhesion, and the effect is β1 integrin-dependent.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, recombinant protein deletion/mutation analysis, adhesion assays, subcellular fractionation\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and domain mapping with RNAi validation, single lab\",\n      \"pmids\": [\"16720730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Maspin binds directly to pro-uPA (K_d ≈ 270 nM), inhibits plasmin-mediated pro-uPA cleavage, and promotes internalization of the uPA/uPAR complex; this requires the maspin RSL P1' Arg340, since R340A mutation abolishes both pro-uPA binding and the maspin effects on pro-uPA cleavage and cell detachment. Maspin also enhances the uPAR–LRP interaction and sustains mature focal adhesion contacts.\",\n      \"method\": \"Biophysical binding assay (K_d determination), plasmin cleavage assay, site-directed mutagenesis of RSL, co-localization immunofluorescence, cell detachment/adhesion assays, Co-IP\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding with K_d measurement, enzymatic inhibition assay, mutagenesis validation, and cellular functional readouts in one study\",\n      \"pmids\": [\"16618739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Intracellular maspin overexpression in endothelial cells induces apoptosis involving changes in Bcl-2 family gene expression and caspase activation; this effect is dependent on the RSL region of maspin and is blocked by Bcl-2 overexpression or caspase inhibitors. Tumor neovessels (but not mature normal vessels) are disrupted by intravascular adenoviral maspin delivery in mice.\",\n      \"method\": \"Adenoviral overexpression in vitro and in vivo, apoptosis assays, caspase inhibitor blockade, Bcl-2 overexpression rescue, maspin RSL deletion mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with Bcl-2 overexpression and caspase inhibitors, RSL mutagenesis, in vivo confirmation; single lab\",\n      \"pmids\": [\"15688005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In non-transformed human epithelial cells (MCF10A, RWPE-1), maspin has an obligate intracellular, nucleocytoplasmic distribution; it is neither glycosylated nor secreted, not present at the cell surface (cell-surface biotinylation negative), not associated with the cytoskeleton, and exists as a soluble monomer. Addition of a signal peptide directs maspin into the secretory pathway producing glycosylation but not secretion.\",\n      \"method\": \"Indirect immunofluorescence, immunoblotting, pulse-chase glycosylation analysis, cell-surface biotinylation, subcellular fractionation, 3D acini differentiation, signal-peptide fusion construct\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods (biotinylation, pulse-chase, fractionation, 3D model) in single rigorous study\",\n      \"pmids\": [\"20123984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Maspin enhances endothelial cell (HUVEC) adhesion through integrin β1 activation, which redistributes vinculin and F-actin and increases integrin-linked kinase (ILK) activity and FAK phosphorylation. During bFGF-stimulated migration, maspin decreases active Rac1 and Cdc42, elevates FAK-Tyr397 phosphorylation, reduces focal adhesion disassembly, and retards EC migration.\",\n      \"method\": \"Integrin activation assays, ILK activity assay, phospho-FAK Western blotting, Rac1/Cdc42 pull-down, F-actin/vinculin immunostaining, HUVEC migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts of integrin signaling, single lab\",\n      \"pmids\": [\"20713357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The G α-helix of maspin is essential and sufficient for inhibiting cell migration and regulating cell adhesion; a 15-mer G-helix peptide mimics maspin's anti-migratory effect, and G-helix mutations abolish it. These G-helix effects depend on β1 integrins. Mutations at the P1 reactive center loop position or an internal salt bridge do not attenuate cell migration inhibition.\",\n      \"method\": \"Site-directed mutagenesis of G-helix, salt bridge, and P1 positions; synthetic peptide; cell migration and adhesion assays; integrin-blocking antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis plus synthetic peptide reconstitution identifies sufficient structural element; β1 integrin dependence confirmed\",\n      \"pmids\": [\"20837467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PAR-1 (thrombin receptor) negatively regulates maspin transcription in metastatic melanoma by reducing binding of Ets-1 and c-Jun to the maspin promoter; PAR-1 silencing increases CBP/p300 expression and decreases p38 activity, leading to enhanced Ets-1/c-Jun binding and maspin re-expression, which reduces melanoma invasiveness.\",\n      \"method\": \"Gene expression profiling, promoter-luciferase reporter, ChIP for Ets-1/c-Jun, CBP/p300 and p38 Western blotting, siRNA silencing, invasion assays, xenograft tumor models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP for transcription factor binding, epistasis by PAR-1 rescue, multiple in vitro and in vivo functional readouts\",\n      \"pmids\": [\"21187389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Maspin inhibits HDAC1 and thereby increases acetylation of Ku70, causing dissociation of Bax from Ku70 and triggering Bax-dependent apoptosis. Maspin was identified as a Ku70-interacting molecule.\",\n      \"method\": \"HDAC1 activity assay, Ku70 acetylation Western blotting, Co-immunoprecipitation of maspin-Ku70 and Bax-Ku70 interactions, cell death assays\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and enzymatic activity assay linking maspin to HDAC1 inhibition and Ku70 acetylation; single lab\",\n      \"pmids\": [\"22076034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SerpinB5/maspin physically interacts with KHDRBS3 and FBXO32 in gastric cancer cells (confirmed by co-immunoprecipitation and yeast two-hybrid); KHDRBS3 in turn interacts with FBXO32 mRNA (RNA Co-IP), and changes in SerpinB5 expression alter FBXO32 mRNA levels 24 h after KHDRBS3 protein levels change.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, RNA co-immunoprecipitation, RNAi knockdown, Western blotting, RT-PCR\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and RNA Co-IP validating yeast two-hybrid hits; single lab\",\n      \"pmids\": [\"21725612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Maspin expression is induced by proteasome inhibitors via a p38MAPK/AP-1 pathway; maspin siRNA attenuates proteasome inhibitor-induced apoptosis, and maspin-transfected prostate cancer cells show enhanced apoptosis with proteasome inhibitors. AP-1 activation by p38MAPK (not ERK1/2 or NF-κB) drives maspin transcription.\",\n      \"method\": \"EMSA, promoter-reporter assays, p38MAPK/ERK/NF-κB inhibitors for pathway epistasis, maspin siRNA knockdown, apoptosis assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding by EMSA, pharmacological epistasis, siRNA validation; single lab\",\n      \"pmids\": [\"17458898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTEN and p53 act in tandem to induce maspin expression under hypoxia: nuclear PTEN complexes with p53, while cytoplasmic PTEN prevents Mdm2 nuclear entry (by attenuating Akt), protecting p53 from degradation. Combined PTEN/p53 presence coordinates maspin and p21 induction. Altering PTEN or p53 expression attenuated maspin induction.\",\n      \"method\": \"Subcellular fractionation, Co-IP of PTEN-p53 complex, Akt inhibition, genetic knockdown of PTEN and p53, immunohistochemistry of xenograft tumors, Western blotting\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic epistasis (double knockdown) and in vivo IHC confirmation; single lab\",\n      \"pmids\": [\"19221500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Maspin enhances sensitivity of prostate cancer cells to hypoxia-induced apoptosis; maspin-overexpressing DU-145 cells show increased apoptosis and reduced tumor growth/vascularity under hypoxia, with suppression of Akt and focal adhesion kinase (FAK) activation as the mechanistic basis.\",\n      \"method\": \"Maspin stable transfection, hypoxia chamber (1% O2), apoptosis assays, phospho-Akt/FAK Western blotting, in vivo xenograft tumor growth and vascularity analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression with in vivo confirmation and defined signaling readout (Akt/FAK); single lab\",\n      \"pmids\": [\"18931702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Maspin downregulation (by shRNA or E2F1-DP1 overexpression) dramatically accelerates cell cycle progression in gastric cancer cells with increased active CDC25C and decreased inactive CDK1, while maspin upregulation retards cell proliferation, establishing maspin as a cell cycle regulator.\",\n      \"method\": \"shRNA knockdown, E2F1-DP1 overexpression, flow cytometry cell cycle analysis, Western blotting for CDC25C and CDK1 phosphorylation states\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal loss-of-function approaches (shRNA and E2F1-DP1 OE) with specific cell cycle molecular readouts; single lab\",\n      \"pmids\": [\"22962304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Myocardin activates maspin transcription through a CArG box in the maspin promoter; this is demonstrated by luciferase reporter assay. Combined treatment with 5-aza-dC/TSA (epigenetic de-repression) and myocardin synergistically enhances maspin re-expression and maspin-mediated apoptosis in MCF-7 breast cancer cells.\",\n      \"method\": \"Luciferase reporter assay with CArG box mutagenesis, myocardin transfection, 5-aza-dC/TSA epigenetic drug treatment, apoptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter element identification by reporter assay with mutagenesis; single lab\",\n      \"pmids\": [\"24607789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EGFR ligands (EGF, TGFα) regulate maspin/SerpinB5 phosphorylation in mammary epithelial cells; EGF specifically induces SerpinB5 nuclear accumulation. At least 8 different SerpinB5 phosphoforms were detected by high-resolution isoelectric focusing during lactation. Amphiregulin autocrine activity maintains basal phosphorylation.\",\n      \"method\": \"High-resolution isoelectric focusing/immunoblot for phosphoform detection, EGF/TGFα treatment, nuclear fractionation/imaging for localization, EGFR ligand blocking experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical detection of phosphoforms plus ligand-stimulated nuclear translocation; single lab, single study\",\n      \"pmids\": [\"27447178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SERPINB5/maspin acts as an adaptor protein in the TRIM21-SERPINB5-GMPS complex: SERPINB5 prevents GMPS from entering the nucleus and recruits TRIM21 (an E3 ubiquitin ligase) to ubiquitinate and degrade GMPS, thereby repressing TP53 expression and promoting radioresistance in nasopharyngeal carcinoma cells.\",\n      \"method\": \"Mass spectrometry identification of TRIM21 targets, Co-immunoprecipitation of TRIM21-SERPINB5-GMPS complex, CRISPR knockout and overexpression, flow cytometry, immunofluorescence for subcellular localization, in vivo xenograft\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of trimeric complex, CRISPR genetics, in vivo confirmation; single lab\",\n      \"pmids\": [\"32005234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Maspin inhibits EMT and angiogenesis in gastric cancer by blocking the ITGB1/FAK signaling pathway; maspin overexpression decreases ITGB1 and p-FAK, reduces Vimentin and VEGF while increasing E-cadherin, and maspin knockdown restores these phenotypes even when ITGB1 is silenced.\",\n      \"method\": \"CRISPR activation, siRNA knockdown, Western blotting, tube formation assay, Transwell invasion/migration, wound healing assay, IHC of patient tissues\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double-siRNA (maspin + ITGB1), multiple cellular functional assays; single lab\",\n      \"pmids\": [\"32409959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Class I HDACs (specifically HDAC1 and HDAC8) repress maspin in prostate cancer cells independent of promoter DNA hypermethylation; HDAC inhibitors (sodium butyrate, TSA) re-express maspin, and this is accompanied by p53 enrichment at the maspin promoter with increased H3/H4 acetylation, suppressing prostate cancer cell proliferation and migration.\",\n      \"method\": \"HDAC inhibitor treatment (sodium butyrate, TSA), ChIP for p53 and acetyl-H3/H4 at maspin promoter, HDAC1/HDAC8 siRNA knockdown, methylation analysis, proliferation and migration assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence for p53 recruitment and histone acetylation, HDAC-specific knockdown; single lab\",\n      \"pmids\": [\"32391971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tamoxifen induces maspin expression through estrogen receptor alpha (ERα) but not ERβ; this requires the ERα LBD-AF2 domain (LBDmtL539A mutation abolishes activation) and cis-elements between -90 and +87 bp of the maspin promoter (not the HRE at -272 bp). The ERα N-terminal AF-1 domain is critical for basal maspin transcription activation.\",\n      \"method\": \"Maspin-luciferase reporter assay, ERα/ERβ reconstitution in cell culture, ERα deletion/point mutants, promoter deletion analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis and domain-mapping by promoter-reporter, single lab\",\n      \"pmids\": [\"15145521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Maspin is secreted as an exosome cargo protein: electron microscopy shows maspin encapsulated within the exosomal membrane. Maspin-devoid exosomes (from maspin-knockdown MCF-10A cells) have significantly reduced suppressive effects on chemotaxis of recipient NIH3T3 fibroblasts, demonstrating that exosomal maspin can suppress tumor-induced stromal responses.\",\n      \"method\": \"Exosome isolation/fractionation, electron microscopy, atomic force microscopy, dynamic light scattering, Western blotting of exosome fractions, maspin siRNA knockdown, NIH3T3 fibroblast chemotaxis assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural visualization by EM, functional knockdown assay in recipient cells; single lab\",\n      \"pmids\": [\"28009978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Maspin re-expression in prostate tumor cells does NOT inhibit tumor growth or metastasis in vivo and does not influence cell migration, invasion, or survival in vitro in a conditional knockout study; maspin knockout mice develop into overtly normal adults, contrary to original reports of embryonic lethality. Bioinformatic analyses show maspin is not commonly under-expressed in cancer.\",\n      \"method\": \"Conditional knockout mouse generation, tumor growth/metastasis assays in vivo, cell migration/invasion/survival assays in vitro, bioinformatic expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple independent in vivo and in vitro experiments with conditional KO model; directly contradicts prior overexpression studies\",\n      \"pmids\": [\"24445777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Maspin deficiency in mice (exon 4 deletion) causes pulmonary adenocarcinoma, mammary myoepithelial hyperplasia, prostatic luminal hyperplasia, and alopecia areata, establishing context-specific tumor suppressor roles for maspin in vivo.\",\n      \"method\": \"Conditional knockout mouse generation (exon 4 deletion), breeding scheme to bypass embryonic lethality, histopathological phenotyping\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — well-characterized KO mouse model with tissue-specific phenotypes; single lab\",\n      \"pmids\": [\"27923833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SERPINB5 promotes invasion and migration of colorectal cancer cells by activating the TNF-α/NF-κB pathway (increasing p-NF-κB/p65, N-cadherin, MMP2, MMP9, VEGFA and decreasing E-cadherin); these effects were reversed by QNZ (NF-κB inhibitor), placing SERPINB5 upstream of NF-κB in this pro-tumorigenic context.\",\n      \"method\": \"Lentiviral overexpression/knockdown, Western blotting, Transwell invasion/migration, proliferation assays, HUVEC tube formation assay, NF-κB pathway inhibitor (QNZ) epistasis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with NF-κB inhibitor and bidirectional expression manipulation; single lab\",\n      \"pmids\": [\"38460302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINB5/maspin is an epithelial-specific, primarily intracellular (nucleocytoplasmic) non-inhibitory serpin that suppresses tumor invasion and angiogenesis through multiple context-dependent mechanisms: extracellularly it binds pro-uPA (K_d ~270 nM) via its reactive site loop to inhibit pericellular proteolysis and cell detachment, and engages β1 integrin through its G α-helix to regulate cell adhesion and migration; intracellularly it inhibits HDAC1 (thereby acetylating Ku70, releasing Bax for apoptosis, and maintaining histone acetylation at epithelial gene loci), and can act as an adaptor in a TRIM21–SERPINB5–GMPS ubiquitination complex; its transcription is activated by p53, p63, TAp63, tamoxifen-bound ERα, and myocardin acting on its promoter, and is silenced by promoter DNA methylation and HDAC1/8-mediated histone deacetylation; it is also secreted as an exosome cargo protein capable of suppressing stromal responses, and a conditional knockout mouse model demonstrates context-specific tumor suppressor roles in lung, mammary, and prostatic epithelia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SERPINB5 (maspin) is an epithelial non-inhibitory serpin that modulates cell adhesion, migration, invasion, angiogenesis, and apoptosis in a context-dependent manner, predominantly as an intracellular nucleocytoplasmic protein [#10, #1]. In non-transformed epithelial cells maspin is an obligate soluble cytoplasmic and nuclear monomer that is neither glycosylated, cytoskeleton-associated, nor secreted via the classical pathway [#10], and EGFR ligands drive its phosphorylation and EGF-stimulated nuclear accumulation [#21]. Extracellularly, maspin binds pro-uPA directly via its reactive-site-loop residue Arg340, inhibiting plasmin-mediated pro-uPA cleavage and promoting uPA/uPAR internalization to restrain pericellular proteolysis and cell detachment [#8], and it physically associates with β1 integrin to regulate adhesion through a function localized to its G α-helix, which is sufficient to reproduce the anti-migratory effect [#7, #12]; downstream it suppresses Rac1/Cdc42 and modulates FAK/ILK and PI3K/ERK signaling [#6, #11]. Maspin's anti-angiogenic activity is mechanistically separable from its anti-motility activity, as RSL mutants that lose anti-motility function retain inhibition of endothelial migration and tube formation [#1]. Intracellularly maspin functions in apoptosis and chromatin-linked regulation by inhibiting HDAC1, which acetylates Ku70 and releases Bax to trigger Bax-dependent death [#14, #9], and it can act as an adaptor in a TRIM21–SERPINB5–GMPS complex that drives GMPS ubiquitination and represses TP53 [#22]. Its transcription is activated by p53, TAp63, tamoxifen-bound ERα, and myocardin, and is silenced by promoter DNA methylation and HDAC1/8-mediated histone deacetylation [#2, #5, #25, #20, #4, #24]. A conditional knockout establishes context-specific tumor suppression in lung, mammary, and prostatic epithelia [#28], though a separate knockout study found no effect of maspin re-expression on prostate tumor growth, invasion, or survival, indicating its tumor-suppressor role is highly context-dependent [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that maspin acts at the cell surface to restrain tumor cell motility and invasion, framing it as a candidate suppressor of carcinoma invasiveness.\",\n      \"evidence\": \"Recombinant protein, time-lapse microscopy, Boyden chamber invasion, and antibody-blocking in mammary carcinoma cells\",\n      \"pmids\": [\"8876194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular surface receptor identified\", \"Mechanism downstream of membrane binding unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Separated maspin's anti-angiogenic activity from its anti-motility activity, showing two genetically dissociable functions.\",\n      \"evidence\": \"Endothelial migration/tube assays, corneal pocket assay, RSL mutagenesis, xenograft\",\n      \"pmids\": [\"10655109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial receptor/target for anti-angiogenic effect not defined\", \"Structural basis of separability unmapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified maspin as a direct p53 transcriptional target, linking its induction to the DNA-damage/tumor-suppressor program.\",\n      \"evidence\": \"Promoter-reporter, EMSA, adenoviral p53, isogenic p53 cell lines\",\n      \"pmids\": [\"10692390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein-level function\", \"Tissue specificity of p53 control unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that maspin transcription is epigenetically gated by DNA methylation and histone acetylation, explaining its silencing in cancers.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP, 5-aza-dC/TSA reactivation, reporter assays in pancreatic cancer cells\",\n      \"pmids\": [\"14670180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the writers/readers targeting the locus\", \"Causal order of methylation vs deacetylation unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected maspin to extracellular uPA-dependent proteolysis and to intracellular Rho-family/PI3K-ERK signaling controlling adhesion and motility.\",\n      \"evidence\": \"ECM/collagen degradation, bone xenograft (uPA); Rac1 pull-down, PI3K/ERK inhibitor epistasis (signaling)\",\n      \"pmids\": [\"12788977\", \"14508113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical maspin-uPA interaction not yet shown at this stage\", \"Link between surface binding and intracellular signaling unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed TAp63 activates maspin via the p53 site, explaining maspin loss when p63 is lost in invasive cells.\",\n      \"evidence\": \"p63 transfection, reporter, EMSA, ChIP, siRNA loss-of-function, invasion assays in lung cancer\",\n      \"pmids\": [\"15466179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of p53 vs p63 in vivo not resolved\", \"Isoform-specific control beyond TAp63 not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the direct biochemical mechanism for extracellular maspin: RSL Arg340-dependent pro-uPA binding that blocks its activation and promotes uPA/uPAR internalization.\",\n      \"evidence\": \"K_d determination, plasmin cleavage assay, R340A mutagenesis, Co-IP, immunofluorescence\",\n      \"pmids\": [\"16618739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with non-secreted intracellular pool not addressed\", \"Stoichiometry within the uPAR-LRP complex unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified β1 integrin as a maspin partner controlling adhesion and mapped a required region (aa 139-225).\",\n      \"evidence\": \"Co-IP, RNAi, deletion mapping, adhesion assays, fractionation\",\n      \"pmids\": [\"16720730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect integrin binding not distinguished\", \"Single lab, no reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Refined the localization model, showing maspin is an obligate intracellular nucleocytoplasmic monomer in non-transformed epithelium, challenging the secreted/cell-surface model.\",\n      \"evidence\": \"Immunofluorescence, pulse-chase glycosylation, surface biotinylation, fractionation, 3D acini, signal-peptide fusion\",\n      \"pmids\": [\"20123984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How intracellular maspin reaches extracellular targets unresolved\", \"Reconciliation with surface-binding reports incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localized maspin's anti-migratory/adhesion activity to the G α-helix, sufficient as a synthetic peptide and dependent on β1 integrins, distinct from the RSL.\",\n      \"evidence\": \"G-helix and P1 mutagenesis, 15-mer peptide reconstitution, integrin-blocking antibodies, migration/adhesion assays; endothelial integrin/ILK/FAK signaling\",\n      \"pmids\": [\"20837467\", \"20713357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of G-helix/integrin contact unknown\", \"Integration of G-helix and RSL functions unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined an intracellular maspin pro-apoptotic mechanism via HDAC1 inhibition, Ku70 acetylation, and Bax release.\",\n      \"evidence\": \"HDAC1 activity assay, Ku70/Bax Co-IP, acetylation Western, cell death assays\",\n      \"pmids\": [\"22076034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct maspin-HDAC1 binding stoichiometry not defined\", \"Generality across cell types not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified maspin protein interactions with KHDRBS3 and FBXO32 linking it to an RNA-binding/ubiquitin-ligase axis in gastric cancer.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, RNA Co-IP, RNAi, RT-PCR\",\n      \"pmids\": [\"21725612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FBXO32 mRNA change unclear\", \"Single lab, mechanism downstream undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded transcriptional control to ERα/tamoxifen and myocardin, mapping responsive promoter elements and domains.\",\n      \"evidence\": \"Promoter-reporter with element/domain mutagenesis, ERα/ERβ reconstitution, myocardin transfection, epigenetic drug synergy\",\n      \"pmids\": [\"15145521\", \"24607789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of these regulators untested\", \"Combinatorial logic with p53/p63 unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A conditional knockout challenged the tumor-suppressor model, finding maspin re-expression did not affect prostate tumor growth, invasion, or survival.\",\n      \"evidence\": \"Conditional KO mice, in vivo tumor/metastasis assays, in vitro migration/invasion/survival, bioinformatic expression analysis\",\n      \"pmids\": [\"24445777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cannot exclude context-specific suppressor roles in other tissues\", \"Mechanism for discrepancy with overexpression studies unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked EGFR signaling to maspin phosphorylation and EGF-driven nuclear accumulation, indicating regulated subcellular partitioning.\",\n      \"evidence\": \"High-resolution IEF phosphoform detection, EGF/TGFα treatment, nuclear fractionation, ligand blocking\",\n      \"pmids\": [\"27447178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of specific phosphoforms unknown\", \"Kinases responsible not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetically established tissue-specific tumor-suppressor phenotypes for maspin loss in lung, mammary, and prostatic epithelia.\",\n      \"evidence\": \"Exon-4-deletion knockout mouse, breeding to bypass lethality, histopathology\",\n      \"pmids\": [\"27923833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular drivers of each tissue phenotype undefined\", \"Reconciliation with the negative conditional KO study unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed maspin is exported as functional exosome cargo capable of suppressing stromal fibroblast chemotaxis, offering a route for non-classical secretion.\",\n      \"evidence\": \"Exosome isolation, EM/AFM, knockdown, recipient NIH3T3 chemotaxis assay\",\n      \"pmids\": [\"28009978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loading mechanism into exosomes unknown\", \"Receptor on recipient cells unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Recast maspin as a molecular adaptor in a TRIM21-SERPINB5-GMPS ubiquitination complex that represses TP53 and confers radioresistance.\",\n      \"evidence\": \"Mass spectrometry, Co-IP of trimeric complex, CRISPR KO/overexpression, localization imaging, xenograft\",\n      \"pmids\": [\"32005234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interfaces not mapped\", \"Tissue generality of this oncogenic role untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reinforced the β1-integrin/FAK axis as a node through which maspin suppresses EMT and angiogenesis, and confirmed HDAC1/8 (not just methylation) as repressors via p53/histone-acetylation at the promoter.\",\n      \"evidence\": \"CRISPRa/siRNA epistasis with ITGB1, functional tumor assays (gastric); HDAC inhibitor and HDAC1/8 knockdown with ChIP (prostate)\",\n      \"pmids\": [\"32409959\", \"32391971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether intracellular or extracellular maspin pool drives these effects unclear\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a pro-tumorigenic context where SERPINB5 drives invasion via TNF-α/NF-κB activation, underscoring its context-dependent duality.\",\n      \"evidence\": \"Lentiviral overexpression/knockdown, NF-κB inhibitor (QNZ) epistasis, invasion/tube formation assays in colorectal cancer\",\n      \"pmids\": [\"38460302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SERPINB5 activates NF-κB undefined\", \"Reconciliation with tumor-suppressor contexts unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How maspin's intracellular nucleocytoplasmic pool, exosomal export, and extracellular receptor engagement are mechanistically unified — and what determines its switch between tumor-suppressive and pro-tumorigenic outputs — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating G-helix/RSL functions\", \"Determinants of context-dependent direction of effect unknown\", \"Mechanism of non-classical secretion vs obligate intracellular localization unreconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [14, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [22, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 21]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 11, 23, 29]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 9, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 5, 25, 20, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 24, 14]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [\n      \"TRIM21–SERPINB5–GMPS complex\"\n    ],\n    \"partners\": [\n      \"PLAU\",\n      \"ITGB1\",\n      \"HDAC1\",\n      \"XRCC6\",\n      \"TRIM21\",\n      \"GMPS\",\n      \"KHDRBS3\",\n      \"FBXO32\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}